2h, 6h-chromeno (7, 6-b)-1, 4-oxazines and processes for their preparation



United States Patent 3,288,788 2H,6H-CHROMENO(7,6-b)-1,4-0XAZINES ANDPROCESSES FOR THEIR PREPARATION George R. Ramage, Kirliburton,Huddersfield, and John Hill, Salford, England, assignors to BengerLaboratories Limited, Holmes Chapel, Cheshire, England No Drawing. FiledJuly 9, 1963, Ser. No. 293,896 Claims priority, application GreatBritain, July 10, 1962, 26,406/ 62 Claims. (Cl. 260-244) The presentinvention relates to new chemical compounds.

It has been found that the new chromone derivatives as hereinafterdefined possess special activity as inhibitors of the antigen-antibodyreaction.

Accordingly the present invention is for the new chroma one derivativesof the following general t'crmula:

or salts or functional derivatives thereof, where R is hydroxy, or aradical NH'R CO 'H, or the radical OR R R wherein R comprises analkylene radical, straight or branched (for example, methylene,ethylene, ethylidene, isopropylene), and R and R are the same ordilferent and comprise hydrogen or .al-kyl groups (for example, methylor ethyl) or together with the nitrogen form a heterocyclic group (forexample, piperidino), and wherein R is hydrogen or a lower alkyl .groupsuch as methyl or ethyl, or it may be an oxygen atom forming a carbonylgroup @O, with the carbon in the ring.

Examples of compounds according to the present invention which may bementioned include 3,4-dihydro-3,6-di0X0-2H,6H-chrornenO(7,6-b)-'1,4-0Xazine 8 carboxylic acid (thecompound of the formula where R is hydroxy and R is a carbonyl oxygenatom) and 3,4-dihydro-3- methyl-6-oxo-2H,6H-chromeno(7,6-b)-1,4-oxazine3 carboxylic acid (the compound of the formula where R is hydroxy and Ris methyl).

Salts of the choromone derivatives which may be mentioned include metal(tor example, alkali metal) and ammonium salts of the carboxylic acidfunction present.

The chromone derivatives of the invention have been shown inexperimental anaphylaxis in animals to inhibit the release of spasmogenswhich normally cfollow the combination of specific antigen withantibody. In man, the pathological eitects which the follow theadministration of antigen to susceptible subjects is markedly inhibited.These compounds are therefore also of value in the treatment of anycondition in which an extrinsic antigen combination wth antibody isprimarily responsble for disease, for example asthma, hay fever,urticaria and the like.

Accordingly one embodiment of the invention is for a pharmaceuticalcomposition which contains a chromone derivative as defined above or asalt or functional derivative thereof and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier may be liquid and/orsolid. The carrier may be for example suitable for the preparation oftable-ts or the like or suitable for the preparation of solutions forinjection, or suitable for the preparation of creams, lotions, pastes orthe like,

The chromone derivatives may also be administered in the form of anaerosol by means of a suitable appliance.

In the case of compounds where R is a carbonyl oxygen atom, a convenientstarting material is S-nitroresacetophenone. One embodiment of theinvention is 3,288,788 Patented Nov. 29, 1966 the process for thepreparation of the chromone derivatives where-in S-n-itroresacetophenoneis reduced catalytic-ally under presure in the presence of Raney nickelto S-aminoresacetophenone, and chloracetylation of the amino groupfollowed by heating with potassium acetate gives 6acety1-3,4-dihydro-7-hydroxy-3-oxo-2H 1,4- benzoxazine which is thencondensed with diethyl oxalate and the resulting diketone is cyclised byheating in a mixture of glacial acetic and hydrochloric acids to give3,4 dihydro-3,6-dioxo-2H,6H-chromeno(7,6-b) 1,4- oxazine-8-carboxylicacid.

Another embodiment of the invention is the process for the preparationof the chromone derivatives wherein S-benzoyloxy-Q-n-itrophenol isreacted with chloroacetone in boiling acetone to give5-'benzoyloxy-Z-nitrophenoxyacetone which, on hydrogenation, forms7-benzoyloxy-3,4 dihydro-B-methylQH 1,4 benzoxazine. Acetylation of thiscompound under Friedel-Crafts conditions also causes debenzoylation, theproduct being 6-acetyl-3,4-dihydro-7- hydroxy-3-methyl2H-l,4-benzoxazine which is condensed with diethyl oxalate togive ethyl-3,4-dihydro-3-methyl6 oxo-ZH,6H-chromen=o-(7,6b)-1,4-ox-azine-8-carboxylate. This ester may be hydrolysed to thecorresponding carboxylic acid by heating with glacial acetic acid andsulphuric acid.

The following examples are given to illustrate the present invention;the parts and percentages are by weight unless otherwise indicated.

Example 1 A solution of 66 parts of S-nitroresacetophenone in 880 partsof acetone was treated with hydrogen at room temperature and 20-30atmospheres, in the presence of Raney nickel. After 1 hour the mixturewas filtered and the filtrate evaporated under reduced pressure to 350parts. 1,000 parts of ether were added and the resulting solutionsaturated with dry hydrogen chloride from which 5 9 parts ofcrudeS-aminoresacetophenone hydrochloride were obtained as a dark brownsolid. 3 parts of the crude hydrochloride were disso'vled in the mimnumamount of water, boiled for 5 minutes with charcoal and filtered. 3parts of anhydrous potassium acetate were added to the cooled filtrateand 2.2 parts of S-alminoresacetophenone separated as a pale yellowsolid. Crystallisation from a large volume of benzene gave golden yellowprisms of melting point 151 C. (with decomposition).

Analysis.Found': C, 57. 8; H, 5.4. Calculated for C 'H NO C, 57.5; H,5.4%.

10 parts of S-aminoresacetophenone and 4.6 parts of chloracetyl chloridewere heated under reflux in 450 parts of dry benzene during 12 hours.The cooled mixture was filtered, and gave 13.25 parts ofS-chloroacetylaminoresacetophenone as a beige solid, melting point 224246 C. which crystallised from ethanol as olT-white prisms, meltingpoint 251 C.

Altalysis.- Found: C, H, 4.4. C10H10NO4C1 requires: C. 49.3; H, 4.1%.

12 parts of S-chloroacetylaminoresacetophenone and 11 parts of anhydrouspotassium acetate were heated under reflux, in 250 parts of ethanol,during 1 hour. parts of water were added, and the mixture Was cooled for10 minutes at 0 C. 8.9 parts of 6-acetyl-3,4-dihydro-7-hydroxy-3-oxo-2H-1,4-benzoxazine were filtered off as a lightbrown solid which crystallised LfI'OIll ethanol as light brown needles,melting point 265 C.

Analysis.Found: C, 57.8; H, 4.2. C H NO requires: C, 58.0; 'H, 4.4%.

A solution of 0.75 part of 6-acetyl-3,4-dihydro-7-hydroxy-3-oxo-2H-l-,4-benzoxazine in 20 parts of diethyl oxalate washeated for 30 minutes on a water-bath with a solution of sodium ethoxide(prepared by dissolving 0.45 part of sodium in 10 parts of ethanol). Theresulting red suspension was allowed to stand during 30 minutes at roomtemperature, filtered, and the solid washed with ether and then added to15 parts of wellstirred 2 N hydrochloric acid. 0.88 part of6-(3-ethoxycarbonyl-3-oxopropionyl) 3,4-dihydro-7-hydroxy-3-oxo-2H-l,4-benzoxazine were obtained as a yellow solid, which crystallisedfrom methanol as pale yellow crystals, melting point 215216 C. (blockpreheated to 160 C.).

Analysis.Found: C, 54.6; H, 4.0. C H NO requires: C, 54.7; H, 4.3%.

3.7 parts of 6-(3-ethoxycarbonyl-3-oxopropionyl)-3,4-dihydro-7-hydroxy-3-oxo-2H-1,4-benzoxazine were heated under reflux with30 parts of glacial acetic acid and 6 parts of concentrated hydrochloricacid during 2 hours. On cooling 2.85 parts of3,4-dihydro-3,6-dioxo-2H,6H- chromeno(7,6-b)-1,4-oxazine-8-carboxylicacid monohydrate separated as a buff-coloured solid which crystallisedfrom methanol as clusters of. small colourless needles, melting point310 C. (with decomposition).

Analysis.-Fund: C, 51.6; H, 3.4. C H NO .H O requires: C, 51.6; H, 3.2%.

Drying for 2 hours at 135 C. and 4 millimetres pressure converted themonohydrate into the anhydrous acid, melting point 305 C. (withdecomposition).

Analysis.Found: C, 55.3; H, 3.1; N, 5.3. requires: C, 55.2; H, 2.7; N,5.4%.

Example 2 A well stirred mixture of 41 parts of -benzoyloxy-2-nitrophenol, 23 parts of anhydrous potassium carbonate, 5 parts ofpotassium iodide, 15.4 parts of chloroacetone and 500 parts of dryacetone wa heated under reflux during 4 hours. The mixture was filteredand the filtrate evaporated almost to dryness. The solid obtained onslurrying with 20 parts of ethanol was filtered off, washed with 20parts of ethanol and crystallised from ethanol to yield 28.5 parts of5-benzoyloxy-Z-nitrophenoxyacetone, melting point 123-124 C.Recrystallisation from ethanol gave cream-coloured crystals, meltingpoint 124 C.

Analysis-Found: C, 60.6; H, 4.1. quires: C, 61.0; H, 4.2%.

A solution of 23.1 parts of 5-benzoyloxy-2-nitrophenoxyacetone in 800parts of methanol was shaken with hydrogen at 70 atmospheres in thepresence of Raney nickel, until no further drop in pressure wasobserved. The mixture was filtered and the filtrate evaporated to about50 parts. On cooling at 0 C., 10.8 parts of 7- benzoyloxy-3,4-dihydro 3methyI-ZH-1,4-benzoxazine separated as a grey crystalline solid, meltingpoint 105- 107 C. Dry hydrogen chloride was passed through the motherliquors and the mixture was cooled. The solid which separated wasstirred into water to give a further amount (0.5 part) of thebeuzoxazine, melting point 104-106 C. Recrystallisation from ethanolyielded colourless rhombs, melting point 106107 C.

Analysis-Found: C, 71.5; H, 5.9. C H NO requires: C, 71.4; H, 5.6%.

A solution of 8.7 parts of 7-benzoyloxy-3,4-dihydro-3-methy1-2H-1,4-benzoxazine in 15 parts of boron trifluoride-acetic acidcomplex was heated during 4 hours on a water-bath. The resulting mixturewas stirred into 50 parts of warm water, filtered, cooled and made alkaline by the addition of potassium carbonate. The precipitate obtainedwas collected, extracted with ether, and the dried ethereal solution wasdistilled to remove the solvent. The brown residue was crystallised frommethanol to give 2.8 parts of 6-acetyl-3,4-dihydro-7-hydroxy-3-methyl-2H-1,4-benzoxazine as green prisms, melting point Ill-113 C.Recrystallisation from methanol atforded yellow-green prisms, meltingpoint 114 C.

Analysis.Found: C, 63.7; H, 6.3; N, 6.7. C H NO requires: C, 63.8; H,6.3; N, 6.8%.

A mixture of 0.5 part of 6-acetyl-3,4-dihydro-7- 4hydroxy-3-methyl-2H-1,4-benzoxazine, 5 parts of diethyl oxalate, andsodium ethoxide (prepared by dissolving 0.25 part of sodium in theminimum amount of ethanol), was heated during 60 minutes on awater-bath. Ether was added and the solid obtained on filtration waswashed with ether and stirred into 10% hydrochloric acid. The mixturewas extracted with ether, the dried ethereal extract was evaporated, andthe residue heated under reflux with 5 parts of saturated ethanolichydrogen chloride for 1 hour. On evaporation of the solution andtrituration of the residue with aquesous sodium carbonate, a yellowsolid was obtained. Crystallisation from ethanol afforded 0.4 part ofethyl 3,4-dihydro-3-methyl-6-oxy- 2H,6H-chromeno(7,6-b)-1,4-oxazine 8carboxylate as brown blades, melting point 188l90 C. which crystallisedfrom ethanol as golden-brown blades, melting point 191-192 C.

Analysis.Found: C, 62.2; H, 5.3; N, 4.8. C H NO requires: C, 62.3; H,5.2; N, 4.8%.

0.3 part of ethyl 3,4-dihydro 3-methyl-6-oxo-2H,6H-chromeno(7,6-b)-1,4-oxazine-8-carboxylate were heated under refluxduring two hours with 2 parts of glacial acetic acid and 2 parts of 4N-sulphuric acid. On cooling, 0.24 part of3,4-dihydro-3-methyl-6-oxo-2H,6H-chromeno(7,6-b)-1,4-oxazine-8-carboxylic acid monohydrate crystallisedas brown rhombs, melting point 285- 287 C. (with decomposition). Themonohydrate was recrystallised from aqueous dioxan to yield orangeplates, melting point 286-287 C. (with decomposition).

AnaZysis.Found: C, 56.2; H, 4.4. C H 'NO .H O requires: C, 55.9; H,4.8%.

Drying for four hours at 135 C. and 5 millimetres pressure converted themonohydrate into the anhydrous acid, melting point 290292 C. (withdecomposition).

Analysis.Found: C, 59.5; H, 4.6. C H NO requires: C, 59.8; H, 4.2%.

Example 3 The clinical evaluation of the compounds was based on theantigen inhalation provocation test on human volunteers who sutfer fromspecific allergic asthma. The degree of asthma provoked by theinhalation of an antigen to which the volunteers are sensitive can bemeasured by repeated estimation of the reduction of air-way resistance.

A suitably designed spirometer was used to measure the forced expiratoryvolume at one second (F.E.V. hence the changes in the air-wayresistance. The antiallergic activity of a compound is estimated fromthe difference between the maximum per cent F.E.V. reduction followingcontrol and test provoca-tions after drug administration conducted underidentical experimental conditions. Thus: Percent protection= Av. max.percent F.E.V.

[ fall control shock Av. max. percent F.E.V.

fall test shock Max. percent F.E.V. fall control shock consisting ofchromone derivatives of the formula:

and alkali metal salts, ammonium salts and lower alkyl esters thereof,wherein R is a member selected from the group consisting of hydroxy,NH-lower alkylene- COOH, O-lower alkylene-NH O-lower alkyleneloweralkylamino, O-lower alkylene-di (lower) alkylamino and -O-loweralkylenepiperidino, and Z is a member selected from the group consistingof methylene, lower alkyl-substituted methylene and carbonyl.

2. 3,4-dihydro-3,6-dioxo 2H,6H chromeno(7,6-b)- 1,4-oxazine-8-carhoxylicacid.

3. Alkali metal salt of 3,4-dihydro-3,6-dioxo-2I-L6H- chromeno(7,6-b-1,4-oxazine-8-carboxylic caid.

4. Ammonium salt of 3,4-dihydro-3,6-dioxo-2H,6H- chromeno (7,6-b-1,4-oxazine-8-carboxylic acid.

5. 3,4-dihydro-3-methyl-6-oxo 2H,6H chr0meno(7,6-b)-1,4-oXazine-8-carboxylic acid.

6. Alkali metal salt of 3,4-dihydro-3-rnethyl-6-oxo-2H,6H-chromeno(7,6-b)-1,4-oxazine-8-carboxylic acid.

7. Ammonium salt of 3,4-dihydro-3 methyl-6-oxo-2H, 6H-chromen0 (7,6-b)-1,4-oxazine-8-carboxylic acid.

8. A process for the preparation of a chromone derivative of theformula:

Z A i A ow.

wherein Z is a member selected from the group consisting of methylene,lower alkyl-substituted methylene and \O/ Cfi (II) wherein Z has theprecedingly-recited significances, with diethyl oxalate and thereaftercyclising the resultant diketone by heating with a mixture of glacialacetic acid and concentrated hydrochloric acid.

9. A process according to claim 8 wherein, when Z is carbonyl, saidcompound of Formula II is prepared by reducing S-nitroresacetophenone toS-aminoresacetophenone, chloracetylating the amino group andsubsequently heating with postassium acetate.

10. A process according to claim 8 wherein, when Z is methylene, saidcompound of Formula II is prepared by reacting5-benzoyloxy-2-nitrophen01 with chloracetone to yield5-benzoyloxy-Z-nitrophenoxy acetone followed by hydrogenation andacetylation.

References Cited by the Examiner Kogura, Nippon Kagaku Zasshi, vol. 80,pp. 1467- 1472 (1959).

WALTER A. MODANCE, Primary Examiner.

R. T. BOND, Assistant Examiner;

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF CHROMONE DERIVATIVESOF THE FORMULA: